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The work, which was carried out in the laboratory of Carl June, M.D.,Director of Translational Research at the Abramson Family Cancer ResearchInstitute at the University of Pennsylvania School of Medicine, incollaboration with Sangamo scientists, was published as an Advance OnlinePublication in Nature Biotechnology(http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1410.html).
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"A ZFN approach represents the 'next generation' of HIV-entry blockingagents and a potentially promising class of anti-HIV compounds," said, Dr.June who is the senior author of the study. "These proof of principle data,together with experience from individuals that carry a natural mutation intheir CCR5 gene suggest that permanent 'knock-out' of the of CCR5 gene isimportant and clinically relevant for long-term resistance to HIV infectionand, we believe, may prove to be more effective than temporary 'knock down'approaches based on small molecule inhibitors, antibodies, antisense or RNAi."
Sangamo's ZFNs are designed to permanently modify the DNA sequenceencoding CCR5, a co-receptor that enables HIV to enter and infect cells of theimmune system. Individuals carrying a naturally occurring mutation of theirCCR5 gene, a variant known as CCR5-delta32, have been shown to be resistant toHIV infection.
"The data described in this paper are an important demonstration of thepotential therapeutic properties of our product," commented Dale Ando, M.D.,Sangamo's vice president of therapeutic development and chief medical officer."We have demonstrated that a single treatment with our CCR5-specific ZFNsgenerates a population of HIV-resistant human T-cells similar to the situationin individuals carrying the natural CCR5-delta32 mutation. ZFN-modificationof these cells is permanent and makes them resistant to HIV. The modifiedcells preferentially survive and expand in an animal after HIV infection,providing a reservoir of healthy and uninfectable immune cells. Furthermore,we observed that animals given the ZFN-modified cells had increased numbers ofCD4 cells and substantially lower levels of HIV in their blood compared toanimals given non-modified cells demonstrating statistically significantprotection from the virus. In an HIV-infected patient, such modified cellscould be available as a protected reservoir within the immune system to fightboth opportunistic infections and HIV itself."
Several major pharmaceutical companies have initiated programs to developsmall molecule or monoclonal antibody approaches to block the binding of HIVto CCR5. However, a small molecule or antibody approach requires the constantpresence of a sufficiently high concentration of these drugs or antibody toblock therapeutically relevant numbers of the CCR5 protein, which is presentin thousands of copies on the surface of each T-cell and other tissues in thebody. One such drug has been approved by the US Food and Drug Administrationwith a "black box" warning, the strongest for prescription drugs, concerningthe risk of liver toxicity and the possibility of heart attacks.
Sangamo's ZFN technology represents a means of potentially circumventingthese limitations or risks by specifically modifying only CD4 T-cells, theprincipal target of HIV pathology, in a one-time exposure of the cells toZFNs. This results in permanent modification of the CCR5 protein such that HIVcannot enter and infect the cells. This approach could pot
